Medicaments

ABSTRACT

Pharmaceutical compositions comprising effective amounts of salmeterol (and/or a physiologically acceptable salt thereof) and fluticasone propionate as a combined preparation for simultaneous, sequential or separate administration by inhalation in the treatment of respiratory disorders.

This application is a continuation of U.S. patent application Ser. No.07/578,601, filed Sept. 7, 1990.

This invention relates to improvements in the treatment of asthma andother respiratory disorders. More particularly, it relates to the use ofa bronchodilator drug in combination with a steroidal anti-inflammatorydrug for the treatment of respiratory disorders such as asthma, and topharmaceutical compositions containing the two active ingredients.

Asthma is a condition characterised by variable, reversible obstructionof the airways which is caused by a complex inflammatory process withinthe lungs. In most cases, this process is initiated and maintained bythe inhalation of antigens by sensitive atopic individuals (extrinsicasthma). However, in some patients it is caused by other mechanismswhich at present are poorly understood but do not involve an allergicprocess (intrinsic asthma). The disease has therefore two components,spasm of the bronchial (or breathing) tubes and inflammation or swellingof the breathing tubes.

Salbutamol, the first highly selective β₂ -adrenoceptor stimulant hasbeen used successfully and effectively by inhalation for the immediaterelief of spasm in asthma. However, when given by inhalation, salbutamolhas usually a four to six hour duration of action, which is too shorteither to control nocturnal asthma or for convenient maintenance of thedisease in some patients.

Anti-inflammatory corticosteroids such as, for example, beclomethasonedipropionate have also been administered by inhalation in the treatmentof asthma, although unlike salbutamol the therapeutic benefits resultingfrom reduced inflammation may not be immediately apparent.

It has been recognized that asthma may be treated by using both abronchodilator for immediate relief and a prophylactic anti-inflammatorycorticosteroid to treat the underlying inflammation. Such combinationtherapy directed at the two main underlying events in the lung (i.e.relief of spasm in the breathing tubes and treatment of inflammation inthe breathing tubes) using a combination of salbutamol andbeclomethasone dipropionate has previously been proposed (Ventide, GlaxoGroup trade mark), but suffers a number of disadvantages in view of theabove-mentioned short duration of action exhibited by salbutamol. Thusthe need for a 4-hourly dosing regimen may discourage effective patientcompliance and also renders the product less than satisfactory in thetreatment of nocturnal asthma since the bronchodilator may not remaineffective for the duration of the night, leading to impaired sleep forasthmatics troubled by nocturnal cough, breathlessness and wheeze.

The present invention is based on the concept of a novel combinationtherapy which has markedly greater efficiency and duration ofbronchodilator action than previously known combinations and whichpermits the establishment of a twice daily (bis in diem--b.i.d) dosingregimen with consequent substantial benefits in, for example, thetreatment of asthma, particularly nocturnal asthma.

Thus we have found that if the β₂ -adrenoreceptor stimulantbrochodilator salmeterol and/or a physiologically acceptable saltthereof is combined with the anti-inflammatory corticosteroidfluticasone propionate in a form suitable for administration byinhalation, the resulting compositions may be administered on a b.i.d.basis to provide highly effective treatment and/or prophylactic therapyfor asthmatics. In particular such administration has been shown to leadto significant improvement in daytime lung function, requirement foradditional symptomatic bronchodilator and almost complete abolition ofnocturnal asthma while giving rise to minimal systemic side effects.

Salmeterol is one of a range of bronchodilators having extended durationof action which is described in British Patent Specification No.2140800, and is systematically named 4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol.Fluticasone propionate is one of a range of topical anti-inflammatorycorticosteroids with minimal liability to undesired systemic sideeffects which is described in British Patent Specification No. 2088877,and is systematically named S-fluoromethyl6α,9α-difluoro-11β-hydroxy-16β-methyl-17α-propionyloxy-3-oxoandros-1,4-diene-17β-carbothioate. We have found these twocompounds to be particularly compatible and complementary in theiractivity and thus highly effective in the treatment of asthma and otherrespiratory disorders.

Thus according to one aspect of the invention there are providedpharmaceutical compositions comprising effective amounts of salmeterol(and/or a physiologically acceptable salt thereof) and fluticasonepropionate as a combined preparation for simultaneous, sequential orseparate administration by inhalation in the treatment of respiratorydisorders.

The invention additionally relates to the use of salmeterol (and/or aphysiologically acceptable salt thereof) and fluticasone propionate inthe manufacture of pharmaceutical compositions as combined preparationsfor simultaneous, sequential or separate administration of salmeteroland fluticasone propionate by inhalation in the treatment of respiratorydisorders.

According to a further feature of the invention there is provided amethod of treating respiratory disorders which comprises thesimultaneous, sequential or separate administration by inhalation ofeffective amounts of salmeterol (and/or a physiologically acceptablesalt thereof) and fluticasone propionate.

Suitable physiologically acceptable salts of salmeterol include acidaddition salts derived from inorganic and organic acids, such as thehydrochloride, hydrobromide, sulphate, phosphate, maleate, tartrate,citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate,4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate,salicylate, acetate, fumarate, succinate, lactate, glutarate, gluconate,tricarballylate, hydroxynaphthalenecarboxylate e.g. 1-hydroxy- or3-hydroxy-2-naphthalenecarboxylate, or oleate. Salmeterol is preferablyused in the form of its 1-hydroxy-2-naphthalene carboxylate salt(hydroxynaphthoate).

For administration by inhalation, the compositions according to theinvention are conveniently delivered by conventional means, e.g. in theform of a metered dose inhaler prepared in a conventional manner or incombination with a spacer device such as the Volumatic (Glaxo Grouptrade mark) device. In the case of a metered dose inhaler, a meteringvalve is provided to deliver a metered amount of the composition. Spraycompositions may for example be formulated as aqueous solutions orsuspensions and may be administered by a nebuliser. Aerosol sprayformulations, for example in which the active ingredients are suspended,optionally together with one or more stabilisers, in a propellant, e.g.a halogenated hydrocarbon such as trichlorofluoromethane,dichlorodifluoromethane, 1,2-dichlorotetrafluoroethane,trichlorotrifluoroethane, monochloropentafluoroethane, chloroform ormethylene chloride, may also be employed. The two drugs may beadministered separately in similar ways.

Alternatively, for administration by inhalation or insufflation, thecompositions according to the invention may take the form of a drypowder composition, for example a powder mix of the active ingredientsand a suitable carrier such as lactose. The powder compositions may bepresented in unit dosage form in, for example, capsules, cartridges orblister packs from which the powder may be administered with the aid ofan inhaler such as the Rotahaler inhaler (Glaxo Group trade mark) or inthe case of blister packs by means of the Diskhaler inhaler (Glaxo Grouptrade mark).

The ratio of salmeterol to fluticasone propionate in the compositionsaccording to the invention is preferably within the range 4:1 to 1:20.The two drugs may be administered separately in the same ratio. Eachmetered dose or actuation of the inhaler will generally contain from 25μg to 100 μg of salmeterol and from 25 μg to 500 μg of fluticasonepropionate. As hereinbefore indicated, it is intended that thepharmaceutical compositions will be administered twice daily.

A suitable daily dose of salmeterol for inhalation is in the range 50 μgto 200 μg.

A suitable daily dose of fluticasone propionate for inhalation is in therange 50 μg to 2000 μg depending on the severity of the disease.

The precise dose employed will of course depend on the method ofadministration, the age, weight and condition of the patient and will bedetermined by the clinician depending on the severity and the type ofasthma.

In order that the invention may be more fully understood, the followingexamples are given by way of illustration only.

EXAMPLE 1 Metered Dose Inhaler

    ______________________________________                                                          Target per                                                                              Per Inhaler                                       Active Ingredient Actuation % w/w                                             ______________________________________                                        Salmeterol        25.0   μg  0.0448                                        (as hydroxynaphthoate)                                                        Fluticasone propionate                                                                          25.0   μg  0.0309                                        Stabiliser        5.0    μg  0.0076                                        Trichlorofluoromethane                                                                          23.70  mg     27.8759                                       Dichlorodifluoromethane                                                                         61.25  mg     72.0588                                       ______________________________________                                    

EXAMPLE 2 Metered Dose Inhaler

    ______________________________________                                                          Target per                                                                              Per Inhaler                                       Active Ingredient Actuation % w/w                                             ______________________________________                                        Salmeterol        25.0   μg  0.0448                                        (as hydroxynaphthoate)                                                        Fluticasone propionate                                                                          50.0   μg  0.0618                                        Stabiliser        7.5    μg  0.0106                                        Trichlorofluoromethane                                                                          23.67  mg     27.8240                                       Dichlorodifluoromethane                                                                         61.25  mg     72.0588                                       ______________________________________                                    

EXAMPLE 3 Metered Dose Inhaler

    ______________________________________                                                          Target per                                                                              Per Inhaler                                       Active Ingredient Actuation % w/w                                             ______________________________________                                        Salmeterol        25.0   μg  0.0448                                        (as hydroxynaphthoate)                                                        Fluticasone propionate                                                                          250.0  μg  0.3088                                        Stabiliser        25.0   μg  0.0309                                        Trichlorofluoromethane                                                                          23.45  mg     27.5567                                       Dichlorodifluoromethane                                                                         61.25  mg     72.0588                                       ______________________________________                                    

EXAMPLE 4 Metered Dose Inhaler

    ______________________________________                                                          Target per                                                                              Per Inhaler                                       Active Ingredient Actuation % w/w                                             ______________________________________                                        Salmeterol        25.0   μg  0.0448                                        (as hydroxynaphthoate)                                                        Fluticasone propionate                                                                          125.0  μg  0.1544                                        Stabiliser        15.0   μg  0.0175                                        Trichlorofluoromethane                                                                          23.56  mg     27.7244                                       Dichlorodifluoromethane                                                                         61.25  mg     72.0588                                       ______________________________________                                    

EXAMPLE 5 Metered Dose Inhaler

    ______________________________________                                                          Target per                                                                              Per Inhaler                                       Active Ingredient Actuation % w/w                                             ______________________________________                                        Salmeterol        100.0  μg  0.1791                                        (as hydroxynaphthoate)                                                        Fluticasone propionate                                                                          250.0  μg  0.3088                                        Stabiliser        25.0   μg  0.0309                                        Trichlorofluoromethane                                                                          23.43  mg     27.4224                                       Dichlorodifluoromethane                                                                         61.25  mg     72.0588                                       ______________________________________                                    

In Examples 1 to 5 micronised fluticasone propionate and micronisedsalmeterol (as the hydroxynaphthoate) are added in the proportions givenabove either dry or after predispersal in a small quantity of stabiliser(disodium dioctylsulphosuccinate, lecithin, oleic acid or sorbitantrioleate)/trichlorofluoromethane solution to a suspension vesselcontaining the main bulk of the trichlorofluoromethane solution. Theresulting suspension is further dispersed by an appropriate mixingsystem using, for example, a high shear blender, ultrasonics or amicrofluidiser until an ultrafine dispersion is created. The suspensionis then continuously recirculated to suitable filling equipment designedfor cold fill or pressure filling of dichlorodifluoromethane.Alternatively, the suspension may be prepared in a suitable chilledsolution of stabiliser, in trichlorofluoromethane/dichlorodifluoromethane.

EXAMPLE 6 Metered Dose Dry Powder Formulation

    ______________________________________                                        Active Ingredient    μg/cartridge or blister                               ______________________________________                                        Salmeterol               36.3                                                 (as hydroxynaphthoate)                                                        Fluticasone propionate   50.00                                                Lactose Ph. Eur.                                                                              to       12.5     mg or                                                       to       25.0     mg                                          ______________________________________                                    

EXAMPLE 7 Metered Dose Dry Powder Formulation

    ______________________________________                                        Active Ingredient    μg/cartridge or blister                               ______________________________________                                        Salmeterol               72.5                                                 (as hydroxynaphthoate)                                                        Fluticasone propionate   50.00                                                Lactose Ph. Eur.                                                                              to       12.5     mg or                                                       to       25.0     mg                                          ______________________________________                                    

EXAMPLE 8 Metered Dose Dry Powder Formulation

    ______________________________________                                        Active Ingredient    μg/cartridge or blister                               ______________________________________                                        Salmeterol               72.5                                                 (as hydroxynaphthoate)                                                        Fluticasone propionate   100.00                                               Lactose Ph. Eur.                                                                              to       12.5     mg or                                                       to       25.0     mg                                          ______________________________________                                    

EXAMPLE 9 Metered Dose Dry Powder Formulation

    ______________________________________                                        Active Ingredient    μg/cartridge or blister                               ______________________________________                                        Salmeterol               72.5                                                 (as hydroxynaphthoate)                                                        Fluticasone propionate   250                                                  Lactose Ph. Eur.                                                                              to       12.5     mg or                                                       to       25.0     mg                                          ______________________________________                                    

EXAMPLE 10 Metered Dose Dry Powder Formulation

    ______________________________________                                        Active Ingredient    μg/cartridge or blister                               ______________________________________                                        Salmeterol               72.5                                                 (as hydroxynaphthoate)                                                        Fluticasone propionate   500.0                                                Lactose Ph. Eur.                                                                              to       12.5     mg or                                                       to       25.0     mg                                          ______________________________________                                    

EXAMPLE 11 Metered Dose Dry Powder Formulation

    ______________________________________                                        Active Ingredient    μg/cartridge or blister                               ______________________________________                                        Salmeterol               145.0                                                (as hydroxynaphthoate)                                                        Fluticasone propionate   250.0                                                Lactose Ph. Eur.                                                                              to       12.5     mg or                                                       to       25.0     mg                                          ______________________________________                                    

In Examples 6 to 11 the active ingredients are micronised and bulkblended with the lactose in the proportions given above. The blend isfilled into hard gelatin capsules or cartridges or in specificallyconstructed double foil blister packs (Rotadisks blister packs, GlaxoGroup trade mark) to be administered by an inhaler such as the Rotahalerinhaler (Glaxo Group trade mark) or in the case of the blister packswith the Diskhaler inhaler (Glaxo Group trade mark).

I claim:
 1. A pharmaceutical composition comprising effective amounts ofsalmeterol or a physiologically acceptable salt thereof and fluticasonepropionate as a combined preparation for simultaneous, sequential orseparate administration by inhalation in the treatment of respiratorydisorders.
 2. A composition as claimed in claim 1 wherein salmeterol ispresent as its 1-hydroxy-2-naphthalenecarboxylate salt.
 3. A compositionas claimed in claim 1 presented in the form of a metered dose inhaler ora metered dry powder composition.
 4. A composition as claimed in claim 1in dosage unit form comprising 25-100 μg of salmeterol or aphysiologically acceptable salt thereof and 25-500 μg of fluticasonepropionate per dosage unit.
 5. A composition as claimed in claim 2presented in the form of a metered dose inhaler or a metered dry powdercomposition.
 6. A composition as claimed in claim 2 in dosage unit formcomprising 25-100 μg of the 1-hydroxy-2-naphthalenecarboxylate salt ofsalmeterol and 25-500 μg of fluticasone propionate per dosage unit.
 7. Acomposition as claimed in claim 6 presented in the form of a metereddose inhaler or a metered dry powder composition.
 8. The use ofsalmeterol or a physiologically acceptable salt thereof and fluticasonepropionate in the manufacture of pharmaceutical compositions as combinedpreparations for simultaneous, sequential or separate administration ofsalmeterol and fluticasone propionate by inhalation in the treatment ofrespiratory disorders.
 9. A method of treating respiratory disorderswhich comprises the simultaneous, sequential or separate administrationby inhalation of effective amounts of salmeterol or a physiologicallyacceptable salt thereof and fluticasone propionate.
 10. A method asclaimed in claim 9 wherein the salmeterol or a physiologicallyacceptable salt thereof and the fluticasone propionate are administeredon a twice daily basis.
 11. A method as claimed in claim 10 wherein theeffective amount of salmeterol or a physiologically acceptable saltthereof is 50-200 μg per day and the effective amount of fluticasonepropionate is 50-1000 μg per day.